Dementia is characterized by progressive cognitive impairment and is the most frequent cause of death in the United States after heart disease, cancer and stroke. The most common cause of dementia is Alzheimer's disease (AD) but many other forms have been identified. Those dementias that have no clear distinguishing histological features remain largely unclassified. However, many dementias including AD exhibit familial clustering. Indeed some cases, particularly those with an early age of onset, show an autosomal dominant pattern of inheritance. Genetic linkage studies have already identified mutations causing Alzheimer's disease, Prion diseases and Huntington's disease. We propose to use a molecular genetic approach to further our understanding of the underlying causes of dementia. During the last twelve months we have identified several families multiply affected by adult onset (late and early onset) dementia. We are collecting family history , clinical and neuropathological information on these families and have begun to collect blood samples for linkage studies. In some of these families a diagnosis of Alzheimer's disease has been made whilst in others either there was no firm diagnosis or a diagnosis of another dementing illness was made. These dementing diseases may represent phenotypic variants of the known causes of dementia or genetically distinct disorders. Two of the families are multiply affected by hereditary dysphasic dementia (HDD), a cortical dementia of adult onset and autosomal dominant inheritance. Clinical and neuropathological investigations describe a unique phenotype that fits within the Pick- Alzheimer spectrum. We will use a genetic linkage strategy to test the known causes of dementia in these and other families e.g., mutations within the amyloid precursor protein (APP) gene and the prion protein gene and linkage to the chromosome 14 familial AD (FAD) locus and the Huntington's locus on chromosome 4. If linkage to the APP gene, the prion protein gene or the HD locus is detected, the gene will be sequenced to identify the mutation causing disease. Families showing linkage to the FAD locus on chromosome 14 will be used for other studies in our laboratory. If these causes of dementia can be excluded, a genetic linkage strategy will be used to map the disease loci. A positional cloning strategy will be used to clone the HDD gene. If the HDD locus is a novel gene, preliminary characterization of the gene and the gene product will be undertaken.